Trichloroethanol and trifluoroethanol topical and percutaneous steroid adsorption promoters

ABSTRACT

DERMAL COMPOSITIONS ARE DISCLOSED WHICH COMPRISE TRICHLOROETHANOL OR TRIFLUOROETHANOL AS ONE COMPONENT OF A VEHICLE HAVING SOLUBILIZED THEREIN A DRUG OR OTHER BENEFICIAL CHEMICAL COMPOUND. ALSO DISCLOSED IS A METHOD FOR ADMINISTERING A DRUG OR OTHER BENEFICIAL CHEMICAL COMPOUND TO THE BODY WHICH COMPRISES CONTACTING THE SKIN WITH THE DRUG OR COMPOUND IN THE PRESENCE OF TRICHLOROETHANOL OR TRIFLUOROETHANOL WHIC ACTS AS AN ABSORPTION PROMOTER TO ENHANCE THE TOPICAL OR PERCUTANEOUS ABSORPTION OF THE ACTIVE DRUG OR COMPOUND.

United States Patent O1 fice 3,787,571 TRICHLOROETHANOL ANDTRIFLUOROETHA- NOL TOPICAL AND PERCUTANEOUS STEROID ABSORPTION PROMOTERSTakeru Higuchi, Lawrence, Kan., assignor to Alza Corporation, Palo Alta,Calif. No Drawing. Filed Nov. 11, 1971, Ser. No. 197,919 Int. Cl. A61k17/00 U.S. Cl. 424-239 3 Claims ABSTRACT OF THE DISCLOSURE Dermalcompositions are disclosed which comprise trichloroethanol ortrifluoroethanol as one component of a vehicle having solubilizedtherein a drug or other beneficial chemical compound. Also disclosed isa method for administering a drug or other beneficial chemical compoundto the body which comprises contacting the skin with the drug orcompound in the presence of trichloroethanol or trifiuoroethanol whichacts as an absorption promoter to enhance the topical or percutaneousabsorption of the active drug or compound.

BACKGROUND OF THE INVENTION This invention relates to a composition andto a method for administering a drug or other beneficial chemicalcompound topically to the body. More especially, the invention concernscomposition and a method for enhancing dermatological or percutaneousabsorption of such active agents in compositions for the use of humansand domestic animals.

It is well known that the outer or surface division of the epidermis,known as the stratum corneum or horny layer of the skin, acts as abarrier to penetration of external substances into the immediate area aswell as into the body. Oftentimes, however, it is desired to increasethe degree of dermatological or percutaneous absorption or penetrationof a particular therapeutically active dermal preparation, as forexample in the treatment of skin disorders, subcutaneous infections,cosmetic effects, or the like.

In this regard, several reagents and methods for increasing thepermeability of the skin have been disclosed in the art. For example,occlusion of the skin with metal guards, plastics, or other wraps hasbeen employed to increase the penetration of various agents into theepidermis. Similarly, an increased rate of absorption into the skin hasbeen produced by adjusting the temperature of the skin and/or byregulating the temperature and relative humidity of the adjacentatmosphere. Most effective, however, have been the recent effortsdirected toward the discovery and application of chemical absorptionpromotors which are employed as integral components of therapeuticallyactive or bio-aifecting compositions. Workers in this area haveexperienced varying degrees of success in their endeavors to locatetruly eifective topical or percutaneous aborption promoters, since agreat number of chemical compounds have been found to promoteabsorption, at least to a degree, as for example in British Pat. No.1,001,949 and U.S. Pat. No. 3,472,931.

3,787,571 Patented Jan. 22, 1974 SUMMARY OF THE INVENTION Accordingly,it is an object of this invention to provide an improved means andmethod for promoting topical and percutaneous absorption of drugs,cosmetics, and other beneficial chemical compounds administered tohumans and domestic animals in the form of topically appliedcompositions.

Another object of this invention is to provide improved topically activetherapeutic and bio-affecting preparations which exhibit increasedabsorption into or through the skin.

In attaining the objects of this invention, one feature resides incompositions containing compounds for and to a method for increasingtopical or percutaneous absorption of drugs, cosmetics and otherbeneficial chemical compounds which comprises contacting the skin with adrug, cosmetic or chemical compound in the presence of a vehicle havingas one component thereof an absorption promoter consisting of eithertrichloroethanol (TCE) or trifinoroethanol ('IFE). The absorptionpromoters of the invention can be used as the sole promoter andsolubilizing agent for the drug, cosmetic or chemical com pound, or theycan be employed together with any additional pharmaceutically acceptablesolvents, vehicles, bases, surface active agents, emulsifiers, and thelike.

Other objects, features, and advantages of this invention will becomemore apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION Percutaneous absorption refers tothe passage of a substance from the surface of the skin through thehorny layer of the epidermis, into the cellular epidermis and from thereinto the corium or dermis. Penetration of the substance through thehorny layer constitutes per cutaneous absorption for the purposes ofthis invention. The passage of the substance on into the corium and intothe systemic circulation is considered to be the eifect, or continuingresult of percutaneous absorption. Once a chemical substance passesthrough the horny layer of the epidermis, there readily occurs furtherabsorption or penetration through the stratum granulosum, stratummalpighii and stratum germinativum, on into the first connective tissuebeneath the epidermis, and thence into the remainder of the body, sincebelow the cellular layer referred to as stratum corneum there is verylittle resistance to penetration or absorption. Absorption into thehorny layer alone, or further into the epidermis, without significantsystem absorption is considered to be topical absorption, and it is alsoreferred to as retention.

In nature, when a penetratable substance is applied to the skin, anextremely small percentage of the substance is absorbed into the hornylayer and retained there. An even smaller percentage of the substanceabsorbed into the horny layer passes therethrough into the underlyinglayers identified above, and thence into the systemic circulation of thehuman or animal. Thus, there is some degree of both natural retentionand percutaneous absorption.

The present invention provides a process whereby this natural rate ofpercutaneous absorption and retention, and the amount of penetratablesubstance actually absorbed or retained are markedly increased. Theseeffects are accomplished by contacting the skin with trichloroethanol ortrifluoroethanol and simultaneously or in the presence thereof with thepreferred drug, cosmetic or beneficial agent.

The substances referred to herein as stable, topically active compoundsare drugs or other beneficial chemical compounds which can be appliedtopically to the skin for the purpose of beautifying surface conditions,medicating surface conditions or diseases, subsurface diseases, orsystemic disturbances, or creating skin conditions helpful inalleviating harmful or annoying external factors. Thus, topically activecompounds include those eliciting a pharmacological or physiologicalresponse either at or near the site of application, as well as at a siteremote therefrom. Drugs, cosmetics and compounds utilized according tothis invention possess the ability to be solubilized or minutelydispersed in trichloroethanol, or trifluoroethanol or in a mixturethereof, thus forming a formulation for administering to the skin forpercutaneous absorption or retention of the administered drug, cosmeticor compound. By the terms solubilize or dispersing is meant that thedrug, cosmetic or chemical compound used herein is dissolved or held insuspension by normal mixing or shaking operations in trichloroethanol,or trifluoroethanol, or a mixture thereof, to the extent of at leastabout 0.01% by weight to about 30% by weight of the drug, cosmetic orcompound in the promoter of choice.

Generally speaking, many drugs are useful in treating surface,sub-surface and systemic conditions by topical application, and the samecan be made more effective if their percutaneous absorption rate orretention rate is increased such that preferred concentrations thereofwill penetrate through the horny layer of the skin, or be retainedtherein, or both. Any of the standard drugs. cosmetics or the like usedto treat the body or skin can be applied to the skin in the presence ofthe absorption promoters of this invention. Drug is used herein in itsbroadest sense as including any composition or substance that willproduce a pharmacologic or physiologic response.

Suitable drugs for use in therapy with the absorption promoters of theinvention include without limitation:

(1) Protein drugs such as insulin;

(2) Desensitizing agents such as ragweed pollen antigens, hay feverpollen antigens, dust antigen and milk antigen;

(3) Vaccines such as smallpox, yellow fever, distemper, hog cholera,fowl pox, antivenom, scarlet fever, dyptheria toxoid, tetanus toxoid,pigeon pox, whooping cough, influenza, rabies, mumps, measles,poliomyelitis, Newcastle disease, etc.,

(4) Anti-infectives, such as antibiotics, including penicillin,tetracycline, chlortetracycline, bacitracin, nystatin, streptomycin,neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, anderythromycin; sulfonamides, including sulfacetamide, sulfamethizole,sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole;anti-virals including idoxuridine; and other anti-infectives includingnitrofurazone and sodium propionate; hexachlorophene, cetyl pyridiniumchloride, pyrithione and its salts, undecylenic acid, and others;

(5) Anti-allergenics such as antazoline, methapyrilene,chlorpheniramine, pyrilamine and prophenpyridamine;

(6) Anti-inflammatories such as hydrocortisone, cortisone,hydrocortisone acetate, dexamethasone, dexamethasone 21 phosphate,fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone21-phosphate, and prednisolone acetate;

(7) Decongestants such as phenylephrine, naphazoline, oxymetazoline andtetrahydrazoline;

(8) Miotics and anticholinesterases such as pilocarpine, eserinesalicylate, carbachol, di-isopropyl fluorophosphate, phospholine iodide,and demecarium bromide;

(9) Mydriatics such as atropine sulfate, cyclopentolate, homatropine,scopolamine, tropicamide, eucatropine, and hydroxyamphetamine;

(l0) Sympathomimeti-cs such as epinephrine, ophedrine, phenylephrine;

(11) Sedatives and hypnotics such as pentobarbital sodium,phenobarbital, secobarbital sodium, codeine, (abromoisovaleryl) urea,carbromal;

(l2) Psychic energizers such as 3 (2 aminopropyl) indole acetate and 3(2 aminobutyl) indole acetate;

(13) Tranquilizers such as reserpine, chlorpromazline, andthiopropazate;

(14) Androgenic steroids such as methyltestosterone and fluoxymesterone;

(15) Estrogens such as estrone, 17 estradiol, ethinyl estradiol, anddiethyl stilbesterol;

(16) Progestational agents such as progesterone, megestrol,melengestrol, chlormadinone, ethisterone, norethynodrel, 19 norprogesterone, norethindrone, medroxprogesterone and 17a-hydroxy-progesterone;

(17) Humoral agents such as the prostaglandins, for example PGE PGE andPGF a;

(18) Antipyretics such as aspirin, sodium salicylate, and salicylarnide;

(l9) Antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide;

(20) Anti-malarials such as the 4-aminoquinolines, 8- aminoquinolines,chloroquine, and pyrimethamine;

(21) Antihistamines such as diphenhydramine, dimenhydrinate,tripelennamine, perphenazine, and chlorophenazine;

(22) Cardioactive agents such as hydroflumethiazide, flumethiazide,chlorothiazide, and triamterene;

(23) Nutritional agents such as vitamins, minerals and other compounds,essential amino acids and essential fats;

(24) Anhidrotic agents such as atropine, aluminum, zinc, zirconium, andother metal salts and complexes;

(25) Odorizing, deodorizing, or odor preventing agents, such asperfumes, aromatic oils, metal salts and complexes, and the like;

(26) Antipruritic such as benzocaine, lidocaine, phenol, methol, etc.;

(27) Antieczemic drugs such as metallic oxides, salts such as zincoxide, sulfur and sulfur containing compounds such as sodium thiosulfateand thioglycollic acid, phenol and other phenolics, inorganic andorganic mercurials, coal tars, etc.;

(28) Agents that improve or elfect the peeling, sloughing,keratinization or follicular character of the skin such as salicylicacid, resorcinol, phenol, sulfur, retinoic acid, benzoyl peroxide,thioglycollic acid, their derivatives and the like;

(29) Other drugs having the same or different physiological activity asthose recited above can be employed together with the absorptionpromoters Within the slope of the present invention. Suitable mixturesof drugs can, of course, be dispensed with equal facility as with singlecomponent systems.

Drugs can be in various forms, such as uncharged molecules, componentsof molecular complexes, or nonirritating, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulphate, phosphate, nitrate,borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs,salts of metals, amines, or organic cations (e.g., quaternary ammonium)can be employed. Furthermore, simple derivatives of the drugs such asethers, esters, amides, etc. which have desirable percutaneousabsorption or retention producing characteristics but which are easilyhydrolyzed by body pH, enzymes, etc., can be employed. Other beneficialchemical compounds may likewise be administered in the presence of theinstant, non-toxic absorption promotors for the purpose of enhancingtheir absorption into or through the skin. Thus, for example, cosmeticagents, moisturizers, skin enrichment and toning agents, coloring andpigmenting agents, bleaching agents, sun screens, pigments and likecompounds which are desirably applied topically to the skin mayadvantageously be combined with the promotors of this invention.

Another application of the present invention resides in patch testingwhich is becoming one of the most widely used methods for testing theskin to determine and identify sensitization and/or irritation potentialto various substances such as drugs, cosmetics, and the like. The patchtest consists of the application to uninjured skin, contiguous to theinvolved area, of substances suspected to be causes of the sensitivityand/or the irritation reaction. This is done by saturating the patch, asmall piece of gauze, with one of these substances, occlusive, orsemiocclusive agents, in a concentration that will not cause irritationin the average person. The patch is then covered by a piece ofimpermeable protective material, such as cellophane, or like polymer,and applied to the skin by adhesive plaster. Unless there is pronouncedirritation, the duration of a given test is typically about 36 to 72hours after which the patch is removed. It can, however, be two to fourdays, or longer, before a positive reaction is observed in the testedarea. By using the absorption promoters of this invention, a suspectedchemical may be applied to the skin, left untouched for only so short aperiod of time necessary for absorption, whereupon the test will becomplete without the necessity of the patient tolerating gauze pads,etc., over an extended period of time.

Both trichloroethanol and trifluoroethanol display a very strong protondonating propensity, and as such, these two compounds singly, ormixtures thereof, are especially suited to promote the absorption ofhydrogenaccepting substances, such as amines, certain ketones, etc., asexemplified by the atropine, griseofulvin, diphenhydramine and the like.This result apparently is achieved by the ability of TCE and TFE toreduce the hydrogen binding tendency of the penetrating drug molecules,and/or the skin and tissues being penetrated. The two promoters also areWell adapted for use in conjunction with hydrogen-donating substancessuch as phenols, prostaglandins, alcohols, salicylic acid,acetaminophen, chloramphenicol and the like. The enhanced degree ofabsorption in this instance is believed to result from mask ing of thefixed hydrogen-donating sites in the dermal tissue by thetrichloroethanol and trifluoroethanol.

The incorporation of emollients such as lanolin and lanolin alcohols andtheir ethoxylated and/ or acetylated products, glycerol, glycols andtheir derivatives, fatty acids, their esters, their alcohols and theirderivatives, into the compositions of the present invention increasetheir percutaneous absorption and retention resulting effects, and alsoresult in improved softening and moisturizing effects.

The absorption promoters can be used as the sole promoter and/orsolubilizing agent for the drug, cosmetic or compounds destined fordermal application. Alternatively, the absorption promoters canconstitute only one component of the preparations. Additional componentsinclude other pharmaceutically acceptable solvents, vehiles, or bases,as well as pharmaceutically acceptable surface active agents,emulsifiers, etc. The present absorption promoters can comprise onecomponent of other pharmaceutical preparations such as lotions, creams,solutions and the like. Similarly, non-liquid preparation, such asjellies can be prepared by adding a thickener, e.g., silica, or anunguent base to prepared liquid preparations. The absorption delayingeifect of these additives may be utilized in preparation of compositionswherein it is desirable to control the rate of absorption.

The present preparations can contain small amounts, for example 0.01% byweight or volume/volume or large amounts of trichloroethanol ortrifluoroethanol, that is up to 99.99% by weight or volume/volume topromote percutaneous absorption or drug retention. However, it isgenerally preferred that preparations contain a higher percentage ofabsorption promoters that the active ingredient. Thus, the preparationsaccording to this invention usually contain from about 50% of theabsorption promoter, and about 0.01 to 30% of the drug. While thepresence of even minute amounts of trichloroethanol and trifluoroethanolwill enhance the absorption, it is readily apparent that their desiredeffect will be substantially diluted, and that the preferred ratiobetween pharmaceutically active ingredient and absorption promoter willbe dictated by the recomended dosage of the active ingredient and thedesired rate of application thereof.

The rate of absorption for the promoter can be measured by various knowntechniques. One technique is the radioactive technique. The use ofradioactive substances has simplified the measurement problems allowingfor more accurate determinations. Labeled compounds containingradioactive carbon atoms have been utilized to determine the rate anddegree of percutaneous absorption as well as retention in the hornylayer. Another method of estimating absorption is to utilize thebiological activity exhibited by the compound. In this manner, thedegree of absorption of applied glucocorticosteroids has been determinedby studying vasoconstriction and blanching of the skin caused when thesesubstances reach the corium. Another example of the utilization ofbiological activity to determine percutaneous absorption is themeasurement of sweat secretion after application of anticholinergics.

In testing, particularly for the degree of the factor relied upon todetermine penetration is the chemical substance which is absorbed ratherthan a factor inherent in the vehicle or absorption medium. Thus, bothin vitro and in vivo tests have been devised for determiningpercutaneous absorption and retention. The general method utilized inthe examples which follow for determining percutaneous absorption by thein vitro method is set out in Us. Pat. No. 3,472,931.

Skin of normal appearance is removed from surgically amputated legs orbreasts and immediately or after a period of refrigeration, cut intosections, wrapped in airtight containers, and placed in a freezer atabout 17 C. to about 22 C. for future use. Under the usual testconditions, at least four specimens are used in these experiments. Theskin is handled as gently as possible to prevent cellular damage, and onremoval from the freezer, thawing is carried out at room temperature forabout one hour. The subcutaneous tissue or fat is cut from the undersurface until the net-like pattern of the dermis is seen, with caretaken to avoid cutting into the corium. Then, the skin is draped withthe epidermis outward, over the mouth of an open glass well which isabout 4 cm. in diameter, and secured in place by an elastic band. Aplastic cylinder is then attached to the epidermis with a standardadhesive. Next, the glass well is connected to a second glass well by aglass tube. The second glass well contains a stopper so that the wellscan be filled with physiological saline that bathes the corium side ofthe skin. The test solution or suspension containing the chemicalcompound, labeled with a radioactive carbon atom is then applied to theepidermis contained within the small plastic cylinder. After givenintervals, about 4 hours, 8 hours, 16 hours, 24 hours or larger,aliquots are removed from the glass well and measured for radioactivity.The amount of the radioactive substance which has penetrated is thendetermined, as measured in a Nuclear-Chicago Co. scintillation counter.Radioactivity is expressed as the number of counts per minute registeredon the apparatus at a constant efiiciency. The percent of applied countsper minute penetration in 24 hours is determined by dividing the totalnumber of counts per minute recovered in 24 hours by the counts perminute applied, then multiplying by 100. The concentration in the salineand the corium is assumed to be the same and the volume added by thecorium to be negligible.

The technique then is briefly to apply radioactive labeled material tothe epidermal side, incubate in a temperature and humidity controlledchamber for about 4 to about 24 hours and take samples of the salinebathing the corium to determine radioactivity in a scintillationcounter. Thus, the percentage of applied material which has penetratedto the saline can be measured at any given time. The in vitro techniqueis modified to determine retention in the horny layer as follows.Similar skin is placed between two aluminum sheets and clamps areapplied. This apparatus is immersed in water at about 60 C. for abouttwo minutes, the metal plates are removed from the skin, and theepidermis with stratum corneum is carefully removed from the dermis in acontinuous sheet.

After the epidermis with stratum corneum is dried on a metal gauze,squares about 1 x 1 cm. are cut from the tissue, and placed on glassslides at about 32 C. and about 50% humidity. About 0.005 ml. each ofsolutions of suspensions containing the chemical compound labeled with aradioactive carbon atom in TCE, and other vehicles, such as ethanol andbenzene, is placed on the stratum corneum side of the l cm. pieces andallowed to remain for 22 hours at about 22 C. and about 50% humiditybefore washing. A group of four squares is usually treated with eachsolvent. After 22 hours the squares are individually Washed for tenminutes in each of three washing fluids: (1) water with detergent, (2)70% ethanol, and (3) benzene. The fluids are constantly stirred duringthe washing process. Following the washing, the squares of tissue areindividually dissolved in 0.5 ml. of methylbenzenethonium chloride,scintillation fluid was added and the radioactivity counted.

.An in vivo technique, described in US. Pat. No. 3,472,931, fordetermining percutaneous absorption utilizing the biological activity ofthe compounds is as follows: Healthy, young, adult male and/or femalsubjects are selected. The volar surfaces of the forearms are used andsolutions or suspensions of corticosteroid compounds are prepared with95% ethanol and TFE in dilutions ranging from about 1:100 to about1:5,000,000. Then 0.02 ml. of the various dilutions are applied from adropping pipette on the flexor aspects of both forearms, slightly spreadover an area of about 1 inch diameter and allowed to dry. The areas areleft undisturbed for about 16 hours, and any sites of vasoconstrictionare then noted. The TFE containing fluid was compared with the non-TFEcontaining fluid by placing each on equivalent areas of the forearms.The presence or absence of the physiologic reaction, i.e.,vasoconstriction, was determined after -a designated interval of time,and if the reaction was present, it was recorded as a positive response.This test can be utilized with corticosteroids as they cause blanchingand vasoconstriction upon reaching the corium. Anti-cholinergics alsoare tested with this procedure by recording the presence or absence ofthe physiologic reaction, for example, the inhibition of sweat mg.

The in vivo technique used to determine retention in the horny layerinvolves a similar method where a solution containing the compoundlabeled with a radioactive carbon atom is applied to the body of animalsor the forearms of human volunteers. The compound is solubilized in TCEand ethanol and in a placebo cream base. A 0.01 cc. aliquot of each isapplied to the forearm, about mg. of the placebo cream base, and it isallowed to remain in place for about 60 minutes. The forearms are thenwashed with soap and water and wiped with wet ethanol sponges.

Surface counts were measured before and after washing procedures withthe gas flow, thin Mylar window, skin probe made by the Nuclear-ChicagoCo. similar to that described in Malkinson, P.D.: Studies on thePercutaneous Absorption of C-14 Labeled Steroids by Use of the Gas FlowCell, J. Invest. Derm., 31.19 (1958). The skin probe had a backgroundcount close to 30 counts per minute and operating at about 10%eificiency. Calculations to determine the amount of retention are madein the same manner as discussed concerning the in vitro method.

The eifect of the promoters upon the rate of percutaneous absorption orretention begins to take place almost immediately upon application ofthe promotor to the skin, and, the following examples are illustrativeof various formulations comprising the promoters for applying drugs,etc. to the skin.

EXAMPLE 1 A steroid solution containing 0.01 to 1000 mg. of an estrogencomponent, 0.01 to 10,000 mg. of a progestational component, 17.0 v./v.of glycerine, 41 v./v. trichlor( ethanol, CCl CH OH, lavender odor 0.05v./v. and distilled water, q.s. to ml. The steroid components are mixedinto the trichloroethanol in which previously the lavender had beendissolved. Next, the glycerine is added with stirring and distilledwater added to volume.

EXAMPLE 2 Following the procedure of Example 1, a steroid solution isprepared comprising 10 mg. of ethynyl estradiol- 3-methyl ether, 200 mg.of 6-chloro-6-dehydro-l7a-acetoxyprogesterone, 17 v./v. of glycerine, 41v./v of trichloroethanol, 0.05 v./v. of lavender odor, and distilledwater to 100 mL, with the mixing of the ingredients as in the example.

EXAMPLE 3 A @pical solution comprising 10 mg. of ethynylestradiol-3-methyl ether and 500 mg. of6a-methyl-l7a-acetoxyprogesterone are dissolved in turn in a portion oftrichloroethanol and then sufiicient trichloroethanol is added toproduce the desired amount of solution, for example q.s. to 100 ml.

EXAMPLE 4 An aerosol liquid spray comprising 10 mg. ethynylestradiol-S-methyl ether, 200 mg. of6-chloro-6-dehydrol7a-acetoxyprogesterone, 10% trichloroethanol, and89.8% of the propellants trichlorofluoromethane anddichlorodifiuoromethane 50/50 is prepared by compound of the aboveingredients and then placing it in an aerosol container.

EXAMPLE 5 Repeating the procedure of Example 4, except that the promotertrifluoroethanol (CF CH OH) is used for the promoter of Example 4, thereis prepared a liquid, aerosol spray formulation.

This invention provides a means and improved method for enhancing thepercutaneous absorption of drugs and other beneficial chemicalcompounds, and it is suitable for employment in conjunction with drugswhich are either hydrogen-accepting or hydrogen-donating. While therehave been shown anddescribed and pointed out the fundamental novelfeatures of the invention as applied to the preferred embodiments, thoseskilled in the art will appreciate that various modifications, changesand omissions in the method for enhancing the percutaneous absorption ofdrugs illustrated and described can be made without departing from thespirit of the invention. It is the intention, therefore, to be limitedonly by the scope of the following claims.

What is claimed is:

1. A pharmaceutical composition of matter comprising a first ingredientselected from the group of absorption promoters consisting oftrichloroethanol, trifluoroethanol, and mixtures thereof and at leastone steroid as, a second ingredient and where the first ingredient is anabsorption promoter for increasing the retention and percutaneousabsorption of an effective amount of the steroid, the second ingredient.

2. A pharmaceutical composition of matter according OTHER REFERENCES toclaim 1 wherein the composition contains about 0.01% 61 to 99.99% of thefirst ingredient, and from 0.01% to 30% ,5351, ggj jjgglgg ik- 7 (1943)The Present of the sterold the seFond i i Hewer et al.: Lancet, 235:1290-1 (1938), Trichloro- 3. A pharmaceutlcal compositron of matteraccording 5 ethanol as Basal Narcotic n to claim 1 wherein thecomposition contains a progesta- Lehman et at L phldrmacoh 63,4534(1938) P Sterold and an istrogemc Stenod and a Pharmaceu'trichloroethanol, tribrornoethariol chloral hydrate tlcally acceptablecarrier. and Bromal Hydrate References Cited 10 SHEP K. ROSE, PrimaryExaminer FOREIGN PATENTS 1,227,617 10/1966 Germany. 1,001,949 8/1965Great Britain. 424- 2, 9, 4s, 88, 89, 91, 92, 65, 66, 67, 68, 17s, 238,

901,674 7/1962 Great Britain. 240, 242, 243, 358

